DHE 45

"Most of us get headaches from time to time. Some are mild. Others cause throbbing pain. They can last for minutes or days. There are many different types of headaches. How you treat yours depends on which kind you have.

D.H.E. 45® (dihydroergotamine mesylate) Injection USP should not be used by patients with documented ischemic or vasospastic coronary artery disease. ( See CONTRAINDICATIONS.) It is strongly recommended that D.H.E. 45® (dihydroergotamine mesylate) Injection USP not be given to patients in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e. g., hypertension, hypercholesterolemia, smoker, obesity ,diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia D.H.E. 45® (dihydroergotamine mesylate) Injection, USP should not be administered. (See CONTRAINDICATIONS)

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiavascular evaluation, it is strongly recommended that administration of the first dose of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received dihydroergotamine mesylate. Because cardiac ischemia can occur in the absence of clinical symptoms consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, in those patients with risk factors. It is recommended that patients who are intermittent long-term users of D.H.E. 45® (dihydroergotamine mesylate) Injection USP and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. The systematic approach described above is currently recommended as a method to identify patients in whom D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may be used to treat migraine headaches with an acceptable margin of cardiovascular safety.

Cardiac Events and Fatalities

The potential for adverse cardiac events exists. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported to have occurred following the administration of dihydroergotamine mesylate injection. Considering the extent of use of dihydroergotamine mesylate in patients with migraine, the incidence of these events is extremely low.

Cerebralhemorrhage subarachnoidhemorrhagestroke and other cerebrovascular events have been reported in patients treated with D.H.E. 45® (dihydroergotamine mesylate) Injection, USP; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the D.H.E. 45® (dihydroergotamine mesylate) Injection USP having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack).

Significant elevation in blood pressure has been reported on rare occasions in patients with and without a history of hypertension treated with dihydroergotamine mesylate injection. D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is contraindicated in patients with uncontrolled hypertension. (See CONTRAINDICATIONS)

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1agonist in a study evaluating subjects undergoing cardiac catheterization.

PRECAUTIONS

General

D.H.E. 45® (dihydroergotamine mesylate) Injection, USP may cause coronary artery vasospasm; patients who experience signs or symptoms suggestive of angina following its administration should, therefore, be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowelsyndrome or Raynaud's syndrome following the use of any 5-HT agonist are candidates for further evaluation. (See

Carcinogenesis: Assessment of the carcinogenic potential of dihydroergotamine mesylate in mice and rats is ongoing.

Mutagenesis: Dihydroergotamine mesylate was clastogenic in twoin vitro chromosomal aberration assays, the V79 Chinese hamster cellassay with metabolic activation and the cultured human peripheral blood lymphocyte assay. There was no evidence of mutagenic potential when dihydroergotamine mesylate was tested in the presence or absence of metabolic activation in two genemutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/HGPRT assay) and in an assay for DNA damage (the rat hepatocyte unscheduled DNA synthesis test). Dihydroergotamine was not clastogenic in the in vivo mouse and hamster micronucleus tests.

Impairment of Fertility: Impairment of fertility was not evaluated for D.H.E. 45® (dihydroergotamine mosylate) Injection, USP. There was no evidence of impairment of fertility in rats given intranasal doses of Migranal® Nasal Spray up to 1.6 mg/day (associated with mean plasma dihydroergotamine mesylate exposures [AUC] approximately 9 to 11 times those in humans receiving the MADE of 4 mg).

Ergot drugs are known to inhibit prolactin. It is likely that D.H.E. 45® (dihydroergotamine mesylate) Injection, USP is excreted in human milk, but there are no data on the concentration of dihydroergotamine in human milk. It is known that ergotamine is excreted in breast milk and may cause vomiting, diarrhea, weak pulse, and unstable blood pressure in nursing infants. Because of the potential for these serious adverse events in nursing infants exposed to D.H.E. 45® (dihydroergotamine mesylate) Injection, USP, nursing should not be undertaken with the use of D.H.E. 45® (dihydroergotamine mesylate) Injection, USP. (See CONTRAINDICATIONS)